title: Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation.
abstract: Signal transducer and activator of transcription (STAT)3, a member of a family of DNA-binding molecules mediating numerous physiological and oncogenic signaling pathways, is a novel target in cancer cells which show high phosphorylation of STAT3. Recently, we identified a novel small-molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. We investigated the mechanisms responsible for the antitumor activity in vitro and in vivo through numerous biochemical and biological assays. Specifically, the effects of STX-0119 on target genes (c-myc, cyclin D1, survivin) and apoptosis induction were analyzed in tumors treated with STX-0119 in vivo. STX-0119 showed strong growth-inhibitory activity against a broad range of hematological cancer cell lines, particularly lymphomas. STX-0119 suppressed the growth of SCC3 cells, a human lymphoma cell line with highly activated STAT3, through apoptosis and down-regulation of STAT3 targets such as c-myc, cyclin D1, survivin and Bcl-xL. Notably, Tyr-705-phosphorylated STAT3 up-regulation was not significantly suppressed by STX-0119, as opposed to other STAT3 inhibitors. STX-0119 demonstrated potent antitumor effects in vivo in SCC3-bearing nude mice by way of the down-regulation of STAT3 target genes and induction of apoptosis in the tumors. Thus, STX-0119 may be a new type of STAT3 inhibitor exhibiting strong antitumor activity.
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Haruo
authors.initials: H
authors.lastname: Miyata
authors.forename: Hidee
authors.initials: H
authors.lastname: Ishii
authors.forename: Chie
authors.initials: C
authors.lastname: Oshita
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Masuda
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000494:pharmacology*; D010766:Phosphorylation; D055503:Protein Multimerization; D011804:Quinolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D011804:Quinolines; D050796:STAT3 Transcription Factor; C559957:STX-0119